Alzheimer′s Disease (AD) is a degenerative central nervous system disorder associated with extensive loss of specific neuronal cells, and characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. The disease currently affects as many as four million individuals in the United States alone. To date, there is no treatment that stops or reverses the disease and it presently causes up to 100,000 deaths annually.
The brains of individuals with AD exhibit neuronal degeneration and characteristic lesions variously referred to as amyloid plaques and neurofibrillary tangles. Currently, the only definitive diagnosis of AD is the presence of these plaques in post-mortem brains. According to the dominant scientific hypothesis for AD, called amyloid cascade or amyloid hypothesis, it is believed that progressive cerebral deposition of particular amyloidogenic peptides, beta-amyloid peptides, play a detrimental role in the pathogenesis of AD and can precede cognitive symptoms and onset of dementia by years or possibly even decades (Hardy J, Selkoe D J, Science. 2002 297(5580): 353-6). Thus prevention of production of these peptides has become the major focus of pharmaceutical industry approaches to treatment of AD.
The Aβ peptides are produced as a result of excessive processing of the amyloid precursor protein (APP), the parent trans-membrane protein found in neurons and other cells (Selkoe, DJ. Trends Cell Biol. 1998, 8(11):447-53). Amyloid plaques are composed primarily of 40 and 42 amino acid peptides (called Aβ40 and Aβ42, respectively) derived from amyloid precursor protein (APP) by sequential proteolysis catalyzed by the aspartyl protease, beta-secretase, followed by presenilin-dependent gamma-secretase cleavage. Aβ42 is more hydrophobic and less soluble than Aβ40 and is the predominant species in amyloid plaques. Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity as well as synaptic loss. Therefore all attention for drug development is focused on inhibiting Aβ42 production rather than any other beta amyloid peptide species (Selkoe D J, Schenk D. Annu Rev Pharmacol Toxicol. 2003; 43:545-84).
There are many reasons and risk factors, which may trigger excessive production of Aβ42. In particular ageing, head injury/trauma, genetics such as Apo E4/4 carriers, cardiovascular disease and type 2 diabetes may all predispose an individual towards higher production of Aβ42 and therefore onset of Alzheimer′s disease. Two molecular events, which may be closely tied to enhanced Aβ42 production and the onset, progression and pathogenesis of the disease are generation of reactive oxygen species (ROS) and reduced energy production by neurons (Moreira P I et al., CNS Neurol. Disord. Drug Targets. 2008; 7:3-10). The generation of ROS and consequent cellular damage/response is thought to contribute too much of the hallmark AD pathology seen in susceptible neurons. Defects in energy production by neurons are observed very early in the disease process. Energy deficits in neuron are defined as a reduction in synthesis of ATP, the molecular form of energy in cells.
There are no known drugs or small molecule compounds which target both of these events, i.e. neuronal oxidative stress and energy deficiency as a method to reduce Aβ42 production and as treatment for his disease. In this invention we describe a series of compounds, which target both these events simultaneously and show that such a compound can reduce Aβ42 production and also improve cognition in an animal model of disease.
It has now been found that pyridine carboxylic acid derivatives, which are novel are capable of inhibiting/reducing the production of Aβ in cells.